Multigene Expression Assays for Predicting Recurrence of Colon Cancer

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based on contract, and individual member benefits must be verified. Wellmark determines medical
necessity only if the benefit exists and no contract exclusions are applicable. This medical
policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

This Medical Policy document describes the status of medical technology at the time the document
was developed. Since that time, new technology may have emerged or new medical literature may
have been published. This Medical Policy will be reviewed regularly and be updated as scientific
and medical literature becomes available.

Description:

Gene expression profiling (GEP) assays have been developed and reported for use as prognostic markers in stage 2 or stage 3 colon cancer. These assays are intended to help identify those individuals who are at high risk for recurrent disease and would be candidates for adjuvant tchemoherapy. The number of gene sequences explored vary depending upon the assay used and may range from as few as 5 to as many as several hundred.

Colorectal cancer is classified as stage 2 when it has spread outside the colon and/or rectum to nearby tissue but is not detectable in the lymph nodes and has not metastasized to distant sites. The primary treatment for stage 2 colon cancer is surgical resection of the primary cancer and colonic anastomosis.

The survival rate following surgery is 75% to 80% at 5 years. Recurrence following surgery is a major concern and is frequently the ultimate cause of death. Patients most likely to benefit from chemotherapy are difficult to identify by standard clinical and pathologic risk factors. Genomic tests are intended to be used as an aid for identifying stage 2 patients most likely to experience recurrence after surgery and most likely to benefit from additional treatment.

For patients with stage 3 colon cancer, current guidelines from the National Comprehensive Cancer Network recommend “6 months of adjuvant chemotherapy after primary surgical treatment.” However, some have questioned the benefit of adjuvant chemotherapy in subsets of patients with stage 3 disease (e.g., stage 3A) whose predicted survival may actually exceed that of some stage 2 patients (e.g., stage 2C).

ColonPRS®:

In 2010 Van Laar reported on a 163-gene expression test using data from 232 colon cancer patients across all stages of disease. ColonPRS® is being marketed as a research use only test and has specific warnings against clinical use.

Coloprint®

Salazar and colleagues in 2010 described the development of an 18-gene expression test (the ColoPrint® test). The test is reportedly able to stratisfy stage II colon cancers into low or high risk. This would determine if adjuvant chemotherapy is necessary. A High Risk result means that a patient with stage II colon cancer has a 20% risk of relapse within 3 years and a 22% risk of relapse within 5 years3 without adjuvant treatment. Validation studies have been published only in abstract form at this time.

Genefx Colon®

In 2011, Kennedy et al. reported on the development of a 634-probe set signature.. Cross-validation studies were used to select an optimal transcript signature for prognostic classification.The authors noted a further retrospective validation of the test in a large cohort of stage II colon cancer samples collected as part of a clinical trial is planned.

OncoDefender

The test is performed by Everist Genomics. It is a 5-gene test reportedly able to accurately predict the risk of recurrence of cancer in patients previously treated with surgical resection(i.e. removal) of a Stage I or Stage II colon cancer tumor or a Stage 1 rectal cancer tumor. However, isolated performance of the test in patients with stage II colon cancer was not reported, and several high-risk findings (bowel obstruction/perforation, and lymphovascular invasion) demonstrated higher hazard ratios than observed using the molecular signature. The study (Lenehan 2012) alluded to but did not directly address clinical utility.

Oncotype DX®

O’Connell et al. in a 2010 described the development of a 12-gene expression test (the Oncotype DX® colon cancer test).. Gene expression was quantitated from microdissected fixed paraffin-embedded primary colon cancer tissue. The test was later reduced the genes to a 7-gene prognostic signature and a separate 6-gene predictive signature. Five reference genes are also included in the assay.

Clinical utility

No studies of a GEP for determining prognosis of patients with stage II colon cancer have been published demonstrating the effect of testing on overall reclassification of patients when compared to existing methods of risk analysis. There is no published information on the impact from use of GEP results on patient outcomes. In the absence of information showing a direct effect on outcomes or establishing a strong chain of evidence that testing would be expected to have a positive net effect on outcomes, clinical utility remains unclear.

A Technical Brief, published by the Agency for Healthcare Research and Quality in December 2012, reviewed the clinical evidence for GEP for predicting outcomes, including benefit from adjuvant chemotherapy, in patients with stage 2 colon cancer. The 4 assays reviewed earlier that are commercially available for clinical use were included in the brief. No prospective studies were identified that assessed change in net health outcome with use of a GEP assay, and no studies were identified that used a net reclassification analysis and subsequently evaluated the impact of the reclassification on net health outcome. Additionally, evidence was limited on the reproducibility of test findings, indications for GEP testing in stage 2 patients, and whether results of GEP assays can stratify patients into groups defined by clinically meaningful differences in recurrence risk.

Summary

The available evidence indicates that gene expression profile (GEP) tests for colon cancer can improve risk prediction, particularly the risk of recurrence in patients with Stage II colon cancer. However, evidence to date is insufficient to permit conclusions on how GEP classification compares with other approaches for identifying recurrence risk in stage II patients or on how GEP classification impacts patient outcomes (clinical utility). There is even less evidence to permit conclusions on how GEP classification compares with other approaches for management of other stages of colon cancer. Therefore, the use of GEP assays to predict the likelihood of disease recurrence for patients with colon cancer, is considered investigational.

Regulatory Status

To date, no gene expression test for evaluation of prognosis in stage II colon cancer has been cleared for marketing by the United States Food and Drug Administration (FDA). These tests are offered as laboratory-developed assays in clinical laboratory improvement amendment (CLIA)-licensed laboratories operated by each company and currently do not require FDA premarket review as a result of enforcement discretion.

ColoPrint (Agendia) quantifies the expression of 18 genes as a prognostic classifier of low versus high recurrence risk.

ColDx (Almac) is a microarray based multigene assay that uses 634 probes to identify patients with stage 2 colon cancer at high risk of recurrence.

In summary, the information from these tests can further inform the risk of recurrence over other risk factors, but the panel questions the value added. Furthermore, there is no evidence of predictive value in terms of the potential benefit of chemotherapy to any of the available multigene assays. The panel believes that there are insufficient data to recommend the use of multigene assays to determine adjuvant therapy.

Prior Approval:

Not applicable

Policy:

Gene expression profile (GEP) assays as a technique for managing colon cancer is considered investigational for all indications, including but not limited to its use for predicting the likelihood of disease recurrence in individuals with colon cancer following surgery.

Gene expression profile (GEP) assays, including but not limited to the following are considered investigational:

Oncotype DX colon cancer assay

ColonPRS

OncoDefender

Genefx colon

Coloprint

The available evidence indicates that gene expression profile tests in patients who have stage 2 or stage 3 colon cancer includes development and validation studies. Relevant outcomes are disease-specific survival, test accuracy, test validity, and change in disease status. The available evidence indicates that GEP tests for colon cancer can improve risk prediction, particularly the risk of recurrence in patients with stage 2 or 3 colon cancer. However, the evidence to date is insufficient to permit conclusions on how gene expression profile (GEP) classification compares with other approaches for identifying risk in stage 2 patients or on how GEP classification impacts patient outcomes (clinical utility). There is even less evidence to permit conclusions on how GEP classification compares with other approaches for management of other stages of colon cancer. The evidence is insufficient to determine the effects of the technology on health outcomes. Therefore, use of these gene expression profile (GEP) assays, including predicting the likelihood of disease recurrence for patients with colon cancer, is considered investigational.

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